[unreadable] The extracellular matrix (ECM) endows the arterial wall with important functional and biomechanical properties. The mechanical properties of the main structural components (elastin and collagen) have long been recognized, but recent studies have additionally identified these ECM components as key regulators of vascular cell phenotype, growth, survival, and apoptosis. Disruption of the ECM and alteration of cell-matrix interactions thus compromise arterial integrity and contribute to altered growth and remodeling (G&R). This exploratory grant will utilize a novel computer-controlled system designed to culture mouse carotid arteries ex vivo for days under precise mechanical environments (pressure, flow and stretch) to study interactions between genetic manipulating components of the elastic fibers and altered pressures in G&R. Specifically, we will utilize carotid arteries from fibrillin-1 (FBN-1) deficient mice, a mouse model for Marfan Syndrome (MFS), to investigate relationships between alterations in the organization of elastic lamina and pressure-induced G&R and, hence the progression of MFS. We hypothesize that the progression of MFS is associated with the inability of the arterial wall to normalize wall stresses in response to perturbations in the mechanical environment, thus leading to a cycle of inappropriate G&R events that ultimately results in dilation and thinning of the arterial wall (i.e., aneurysm and dissection). The specific aims that we will pursue to test this hypothesis are: (1) To quantify differences in G&R in carotid arteries from 6 wk old wildtype and FBN-1 deficient mice in culture for 0,12, 24, 48 and 72 hours at a mean pressure of either 80 or 120 mmHg plus normal flow. (2) To quantify differences in G&R in carotid arteries from 8 wk old wildtype and FBN-1 deficient mice in culture for 0-72 h at 80 and 120 mmHg. (3) To utilize the data from Aims 1 and 2 to evaluate a new mathematical model that we developed for arterial G&R. The 6 and 8 wk animals represent distinct differences in the elastic network: normal elastic lamina but compromised cell matrix interactions vs. fragmented elastic fibers and smooth muscle hyperplasia, respectively. Together, these 3 aims will yield the first correlation of altered mechanical properties with alterations in vascular organization at multiple stages in the development of MFS-type diseases. Moreover, this will be the first assessment of diminished capacities of vessels, at different stages of disease progression, to adapt to altered mechanical loads. [unreadable] [unreadable]